Antibody Landscape following Human Norovirus Infection and Vaccination

摘要 人类诺如病毒(HuNov)是急性非细菌性流行性胃肠炎的主要原因，导致 每年约有20万人死亡，主要发生在婴儿、老年人和免疫抑制人群中。胡诺夫病毒疫苗正在研发中 但结果喜忧参半，部分反映了抗原资历、病毒多样性和逃逸。我们的 前提是对病毒类型的功能、表位特异性和原子水平的了解 引起中和抗体的病毒粒子中广泛的交叉反应表位将揭示 保护性体液免疫，而体液免疫又是设计更有效的免疫原和 疫苗接种策略。因此，我们的计划旨在为广泛的发展提供批判性信息 针对高度流行、医学上重要的II组毒株的有效HuNoV疫苗(GII.4和GII.2)。 为了实现这些目标，我们从接种疫苗的人群中获得了相关的按时间排序的样本集， 自然感染和人类挑战研究，在整个计划中被用来阐明 管理保护性免疫、病毒逃逸和大流行毒株出现的基本机制。我们 我还召集了一个由知名专家组成的补充小组，以阐明HuNov的基本问题 血清学免疫，识别以特定类型和广泛保护为目标的关键中和表位 免疫，并揭示了控制HuNov中和、抗原优先和广泛的分子机制 保护豁免权。此外，该计划旨在将这些新发现转化为改进的第二 世代结构导向的HuNoV疫苗免疫原，旨在提高广度和 与保护性免疫相关的体液免疫反应的持久性。为了实现这些目标， 该计划有三个具体目标。在目标1中，我们将定义HuNov特异性血清学抗体库和 生产重组抗体，用于详细的结构和分子分析。在目标2中，我们确定特定类型 并广泛交叉中和抗体，并使用分子方法来识别关键的相互作用表位。在……里面 目的3.利用衣壳的P结构域解析几种相关抗体的原子级结构 蛋白质描绘HBGA阻断和中和的结构基础并使用结构导向 增加免疫原性广度和抗原稳定性的策略，从而改善疫苗在体内的功能。

Abstract Human noroviruses (HuNoV) are the major cause of acute non-bacterial, epidemic gastroenteritis, resulting in ~200,000 deaths/year, mostly in infant, elderly and immunosuppressed groups. HuNoV vaccines are under development but the results are mixed, in part reflecting antigenic seniority, virus diversity and escape. Our premise is that the function, epitope specificity and atomic level understanding of the virus type specific and broadly cross reactive epitopes in the virion that elicit neutralizing antibody will reveal the mechanisms of protective humoral immunity, which in turn is required for the design of more effective immunogens and vaccination strategies. Consequently, our program is designed to critically inform the development of broadly effective HuNoV vaccines that target highly prevalent, medically important genogroup II strains (GII.4 and GII.2). To achieve these goals, we have relevant time-ordered sample sets from cohorts of vaccinated individuals, natural infections and human challenge studies which are leveraged throughout the program to elucidate the fundamental mechanisms governing protective immunity, virus escape and pandemic strain emergence. We have also assembled a complementary group of renown experts to elucidate the essential issues in HuNoV serological immunity, identify the key neutralizing epitopes targeted by type specific and broadly protective immunity, and reveal the molecular mechanisms governing HuNoV neutralization, antigenic seniority and broad protective immunity. Moreover, the program is designed to translate these novel findings to improved 2nd generation structure-guided HuNoV vaccine immunogens which are designed to improve the breadth and durability of humoral immune responses associated with protective immunity. To achieve these goals, the program has three specific aims. In aim 1, we will define the HuNoV-specific serological antibody repertoire and produce recombinant antibodies for detailed structure and molecular analyses. In aim 2, we identify type specific and broadly cross neutralizing antibodies and use molecular approaches to identify key interacting epitopes. In aim 3, we will solve the atomic level structure of several relevant antibodies with the P domain of the capsid protein to delineate the structural basis for HBGA blockade and neutralization and use structure-guided strategies to increase immunogenic breadth and antigen stability, leading to improved vaccine function in vivo.